This invention relates to sustained release formulations for the safe and efficacious administration of fluoxetine for, among other things, the treatment of depression. More particularly, the invention relates to novel methods, compositions, and devices for transdermally administering fluoxetine to a subject through a body surface or membrane over a sustained time period. A preferred embodiment is directed to the transdermal administration of fluoxetine at reduced skin irritation levels.
Fluoxetine, (xc2x1)-N-methyl-xcex3-[4-(trifluoromethyl)-phenoxy]benzenepropanamine, is one of the 3-aryloxy-3-phenylpropylamine compounds described in U.S. Pat. No. 4,314,081. Additionally, U.S. Pat. No. 4,626,549 discloses a method of blocking the uptake of monoamines such as serotonin by brain neurons in animals comprising administering a xe2x80x9cmonoamine blocking amountxe2x80x9d of a 3-aryloxy-3-phenylpropylamine compound, such as fluoxetine. It is a potent, highly selective reuptake inhibitor of serotonin (5-hydroxytryptamine) and is indicated for the treatment of depression and obsessions and compulsions related to obsessive-compulsive disorder (OCD). As an antidepressant or for the treatment of OCD, fluoxetine is administered orally as a solution or in tablets as fluoxetine hydrochloride (Prozac(copyright)) in 10 mg or 20 mg daily doses and has an elimination half-life of from 1-9 days, averaging about 2-3 days. Other methods for the production of fluoxetine and new intermediates are disclosed in U.S. Pat. No. 5,225,585. All of the above mentioned patents are hereby incorporated in their entirety by reference.
Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. The delivery of the S(+) enantiomer is disclosed in the prior art. For example, U.S. Pat. No. 5,104,899 discloses a method of treating depression in a human patient comprising administering the S(+) enantiomer of fluoxetine in substantially optically pure form. PCT application WO 95/28152 discloses methods for treating or improving memory, and for treating sexual dysfunction, while avoiding the unwanted adverse toxic or psychological effects associated with the racemic mixture of fluoxetine, comprising administering a therapeutically effective amount of S(+) fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its R(xe2x88x92) stereoisomer.
The use of fluoxetine for indications other than treating depression is also disclosed in the following: U.S. Pat. Nos. 4,594,358, 4,647,591, 4,683,235, 4,940,585, 4,999,382, 5,151,448, 5,356,934, 5,446,070, 5,589,511, and PCT Application WO 92/18005. Transdermal delivery as a route of administering fluoxetine is mentioned in these patents, though specific formulations or delivery regimens are nowhere disclosed. Other uses of fluoxetine are disclosed in U.S. Pat. Nos. 4,035,511, 4,083,982, 4,329,356, 4,444,778, 4,590,213, 4,895,845, and 5,589,512, all of which do not disclose the transdermal administration route.
Additionally, U.S. Pat. No. 5,601,839 discloses transdermal formulations for enhancing dermal penetration of a basic drug, including fluoxetine, comprising a matrix formulation comprising an amount of the basic drug and a permeation enhancer consisting essentially of triacetin in a polymer layer, preferably a pressure sensitive adhesive.
The oral administration of fluoxetine in the treatment of depression is initiated with a 20 mg/day dose administered in the morning. If no improvement is observed over several weeks, the dosage may be increased, though not to exceed 80 mg/day. Doses above 20 mg/day should be administered once a day in the morning or by a b.i.d. schedule (morning and noon).
The transdermal route of parenteral delivery of drugs and other biologically active agents (xe2x80x9cagentsxe2x80x9d) has been proposed for a wide variety of systemically acting and locally acting agents on either a rate-controlled or non-rate-controlled basis and is described in numerous technical publications such as the following: U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,573,995; 4,588,580; 4,645,502; 4,704,282; 4,788,062; 4,816,258; 4,849,226; 4,904,475; 4,908,027; 4,938,759; 4,943,435; 5,004,610; 5,122,382; 5,141,750; 5,314,694; and 5,342,623, the disclosures of which are incorporated in their entirety herein by reference.
When first investigated in depth in the late 1960""s, the transdermal route of administration appeared to offer many advantages, particularly with respect to agents that had short half lives and therefore required frequent, repeated dosing or were subject to a high degree of first-pass metabolism by the liver when orally administered. The peaks and valleys in blood concentration resulting from frequent periodic doses of short half-life agents would be eliminated and replaced by substantially constant plasma concentration. This would not only improve individual compliance but also would eliminate the alternating periods of high side-effects and ineffective blood concentrations associated with period dosing. Administering the agent through the skin directly into the blood stream would also eliminate first-pass metabolism of orally administered agents.
It was initially assumed, theoretically, that any short half-life agent of high potency and skin permeability would be suitable for safe and effective transdermal administration. This assumption, however, has not been proven true.
The failure of the transdermal route to fulfill the initial expectations of its potential as an administrative portal was primarily due to the incredible variety of properties with which nature has endowed the skin to permit it to perform its function as the primary barrier to prevent the ingress of foreign substances into the body. See Transdermal Drug Delivery: Problems and Possibilities, B. M. Knepp, et al, CRC Critical Reviews and Therapeutic Drug Carrier Systems, Vol. 4, Issue 1 (1987) and Transdermal Delivery Systems: A Medical Rationale, Gary W. Cleary, Topical Drug Bioavailability. Bioequivalence, and Penetration, Plenum Press, 1993.
Thus, the transdermal route of administration, rather than being available to every short half-life agent of high potency and skin permeability, was found to be available only to those few agents that possess the proper combination of a host of characteristics, most of which are unpredictable, required to render the agent suitable for safe and effective transdermal administration.
The most significant of these characteristics are the following:
1. Skin Permeability. The permeability of the skin to the agent must be sufficiently high so that the agent can be administered at a therapeutically effective rate through an area of skin no greater than about 200 cm2 and preferably no greater than 50 cm2. The person-to-person variation in skin permeability at similar sites should also be considered. U.S. Pat. Nos. 4,568,343, 4,746,515, 4,863,738, 4,865,848, 4,888,354, 5,378,730, 5,641,504 and WO 95/09006, WO 95/01167, WO 96/37231, and WO 96/40259 are related to various compositions and methods for enhancing permeation of drugs through the skin and are hereby incorporated in their entirety by reference.
2. Skin Binding. The skin beneath the transdermal delivery device has the capability of creating a skin depot of drug by absorbing, adsorbing, or binding a certain amount of agent. The amount of agent so bound must be supplied to the skin before the agent can be delivered into the blood stream at steady, therapeutically effective rates. If large amounts of the agent are bound in the skin, significant delays in the onset of therapeutic effect (xe2x80x9clag timexe2x80x9d) will be observed together with corresponding delays and termination of effect upon removal of the device. The potential also exists for toxic quantities of potent agents to be contained within the skin beneath the device. Skin binding is not related to skin permeability. Agents that are highly permeable may also be highly bound causing a lag time sufficiently long as to render them unsuitable for their intended use.
3. Irritation. The skin reacts to many topically applied substances, particularly those maintained under occlusion, by blistering or reddening accompanied by unpleasant burning, itching, and stinging sensations. Animal models are used to screen for irritation. Animal models, however, often produce both false positives and false negatives. There is also a wide interpersonal variation in susceptibility to irritation. An agent must be minimally irritating in a large percentage of the potential individual population in order to be suitable for safe and effective transdermal administration. U.S. Pat. Nos. 4,552,872, 4,756,710, 5,028,431, 5,130,139, 5,160,741, and 5,451,407 are directed to overcoming problems associated with skin irritation associated with transdermal drug delivery and are hereby incorporated in their entirety by reference.
4. Sensitization. Sensitization is an allergic reaction which is induced when an agent is first applied to the skin and is elicited upon continued exposure which may occur immediately or after a long period of seemingly harmless exposure.
The sensitization may be local, elicited by topical exposure, which manifests itself as contact dermatitis accompanied by blistering, itching, reddening and burning at the site of application. More seriously, the sensitization may be systemic, elicited by topical application but manifesting itself by more general allergic reactions at sites other than the site of application. Most seriously, the systemic sensitization may be elicited by oral or intravenous administration of the drug. If the latter occurs, the individual will be unable to take the drug by any route of administration.
Animal models are used to screen for sensitization. Animal models, however, produce both false positives and false negatives. There is also a wide variation in the allergic reaction between individuals as well as between sexes, races and skin types. It is obvious that a useful transdermal agent must be minimally sensitizing in a large percentage of the potential individual population. U.S. Pat. Nos. 5,000,956, 5,049,387, 5,120,145, and 5,149,539 are directed to overcoming sensitization problems associated with transdermal drug delivery by the coadministration of a corticosteroid and are hereby incorporated in their entirety by reference
5. Pharmacokinetic Properties. The half-life of an agent is the time after administration that half of the amount administered has been eliminated from the body. Because blood concentrations of continuously administered agents will continue to increase for approximately five half-lives before steady-state constant blood concentrations are achieved, an agent must have a relatively short half-life to be suitable for continuous transdermal administration. The transdermal half-lives of most agents have not been determined. When half-lives of agents determined from intravenous administration are compared with half-lives determined from transdermal administration, the transdermal half-lives are generally longer but there can be wide variation in half-life between individuals based upon factors such as age, sex, health, and body type.
6. Pharmacodynamic Properties. Constant blood levels may not produce the desired therapeutic effects. For example, a therapeutic effect may only be observed at peak blood concentration obtained from bolus dosing but the peak blood or plasma concentration cannot be maintained because of side effects associated therewith. Also, continuous administration of many agents produces tolerance that may require either some agent-free interval or continually increasing and therefore potentially hazardous doses of the agent.
7. Potency. Although a certain degree of potency is required for transdermally administered agent to be effective, it is also possible for an agent to be too potent. As potency increases, lower blood concentrations are required and much smaller quantities are administered. Because of normal inter-individual variations and skin permeability, it may not be possible to precisely control whether a individual is receiving 1 xcexcg/hr or 2 xcexcg/hr, for example. For a highly potent agent, a 1 xcexcg/hr administration may be totally ineffective and a 2 xcexcg/hr rate fatal. Thus, the therapeutic index of an agent, which is the ratio of toxic blood concentration to the therapeutic blood concentration, becomes extremely significant. A highly potent agent should also have a relatively wide therapeutic window in order to be suitable for transdermal administration.
8. Metabolism. One of the perceived advantages of transdermal administration was that it avoided the xe2x80x9cfirst-passxe2x80x9d metabolism of the agent by the liver that is associated with oral administration. It has now been recognized, however, that the skin is also a large metabolizing organ in the body for some drugs. Thus, although first-pass metabolism that occurs after an orally administered agent enters the blood stream can be avoided, skin metabolism, which occurs before the agent enters the bloodstream, cannot be avoided. Skin metabolism is capable of creating metabolites that are inert, irritating, toxic, or comparable in biological activity to that of the agent. An agent, to be suitable for transdermal administration, must have the metabolic properties that are consistent with its therapeutic use on continuous administration.
The above summarizes the primary characteristics that effect suitability of an agent for transdermal administration that have been recognized to date. There are undoubtedly others, some of which have not yet been recognized, and, in order for an agent to be suitable for transdermal administration, it must possess the right combination of all these characteristics, a combination of which, as illustrated by the very few drugs that are now suitable for administration from transdermal delivery devices, is quite rare and unpredictable.
As used herein, the term xe2x80x9cbioequivalentsxe2x80x9d intends that there is greater than 90% probability that the bioavailability is 80-125% and the minimum and maximum blood or plasma concentrations are 80-125% of the referenced dose.
As used herein, the term xe2x80x9cfluoxetinexe2x80x9d intends not only the basic form of fluoxetine but also pharmaceutically acceptable salt forms of fluoxetine, the R or S enantiomers of fluoxetine, either individually or as a racemic mixture, and to mixtures thereof.
As used herein, the term xe2x80x9cfluoxetine therapyxe2x80x9d intends all medical conditions for which fluoxetine is or will be indicated, including, without limitation, for the treatment of depression and obsessive-compulsive disorder.
As used herein, the term xe2x80x9cindividualxe2x80x9d intends a living mammal and includes, without limitation, humans and other primates, livestock and sports animals such as cattle, pigs and horses, and pets such as cats and dogs.
As used herein, the term xe2x80x9cirritation-reducing amountxe2x80x9d intends an amount of an anti-irritant which reduces skin irritation throughout a substantial portion of the administration period.
As used herein, the term xe2x80x9cpermeation enhancementxe2x80x9d intends an increase in the permeability of skin to fluoxetine and/or anti-irritant in the presence of a permeation enhancer as compared to permeability of skin to fluoxetine and/or anti-irritant in the absence of a permeation enhancer.
As used herein, the term xe2x80x9cpermeation enhancerxe2x80x9d intends an agent or a mixture of agents which acts to increase the permeability of the skin to fluoxetine and/or anti-irritant.
As used herein, the term xe2x80x9cpermeation-enhancing amountxe2x80x9d intends an amount of a permeation enhancer which provides permeation enhancement throughout a substantial portion of the administration period.
As used herein, the phrase xe2x80x9cpredetermined area of skinxe2x80x9d intends a defined area of intact unbroken skin or mucosal tissue. That area will usually be in the range of about 5 cm2 to about 100 cm2.
As used herein the term xe2x80x9csaltxe2x80x9d intends, but is not limited to, pharmaceutically acceptable organic or inorganic salts. Typical inorganic salts include hydrogen halides such as hydrochlorides, carbonates, phosphates, sulfates, hydrogen sulfates, hydrobromides, nitrates, and sulfides. Organic salts includes, but are not limited to, acid addition salts including salts of monocarboxylic and polycarboxylic acids such as the acetate, maleate, and citrate.
As used herein, the phrase xe2x80x9csustained time periodxe2x80x9d or xe2x80x9cadministration periodxe2x80x9d intends at least about 8 hours and will typically intend a period in the range of about one to about seven days.
As used herein, the term xe2x80x9ctherapeutically effective amountxe2x80x9d intends the dose of fluoxetine and/or its active metabolite, norfluoxetine, that provides fluoxetine therapy, in the case of adult and juvenile humans, the optimum dosage range is the equivalent of the oral dose of about 5-80 mg fluoxetine per day.
As used herein, the term xe2x80x9ctherapeutically effective ratexe2x80x9d intends a rate of fluoxetine and/or its active metabolite, norfluoxetine, delivery effective to achieve therapeutic blood or plasma levels in an individual during the administration period and is typically within the range of 250-3200 xcexcg/hr.
As used herein, the term xe2x80x9ctherapeutic blood or plasma levelxe2x80x9d intends the level of fluoxetine and/or its active metabolite, norfluoxetine, in blood or plasma that achieves a therapeutic effect for the desired fluoxetine therapy.
As used herein, the term xe2x80x9ctransdermalxe2x80x9d intends both percutaneous and transmucosal administration, i.e., passage of fluoxetine through intact unbroken skin or mucosal tissue into the systemic circulation.
One aspect of this invention is directed to a method of transdermally administering a drug having a relatively long half-life.
Another aspect of this invention is to provide sustained release formulations to administer a therapeutically effective amount of fluoxetine and/or its active metabolite, norfluoxetine, over an administration period.
More specifically, it is an aspect of this invention to provide compositions and methods for the transdermal delivery of fluoxetine and/or its active metabolites, and delivery systems for effecting the same, which are suitable for the transdermal administration of fluoxetine and/or its active metabolites continuously through a body surface or membrane at a therapeutically effective rate in order to achieve and maintain therapeutic blood or plasma levels in an individual.
Another aspect of this invention is to provide compositions, devices, and methods for transdermally administering fluoxetine at reduced skin irritation levels.
Another aspect of this invention is to improve patient compliance of patients in need of fluoxetine therapy by providing compositions, devices, and methods for the transdermal administration of fluoxetine at a therapeutically effective rate.
Yet another aspect of this invention is directed to compositions, devices, and methods for the transdermal administration of fluoxetine at reduced skin irritation levels together with a suitable permeation enhancer.
According to this invention, it has been discovered that fluoxetine can be safely and efficaciously administered transdermally at a therapeutically effective rate to provide, among other things, treatment for depression, when administered alone or when coadministered with a suitable permeation enhancer. A preferred embodiment is directed to transdermally administering a therapeutically effective amount of fluoxetine at reduced skin irritation levels wherein fluoxetine is coadministered from a transdermal drug delivery device containing a pharmaceutically acceptable salt of fluoxetine, an anti-irritant, and a permeation enhancer in order to provide systemic administration of fluoxetine.
These and other aspects of the present invention will be readily apparent from the description and accompanying figures that follow.